U.S. patent number 4,431,004 [Application Number 06/315,282] was granted by the patent office on 1984-02-14 for implantable glucose sensor.
Invention is credited to Samuel P. Bessman, Ennis C. Layne, Lyell J. Thomas.
United States Patent |
4,431,004 |
Bessman , et al. |
February 14, 1984 |
Implantable glucose sensor
Abstract
A method and apparatus for more accurate measurements of the
glucose content in body fuids by sensing the absolute level of
oxygen concentration in the fluid and correcting the output
differential measurement indicative of the glucose content in the
fluid according to the absolute level of oxygen. In the two
electrode systems known to the art, the unaltered oxygen electrode
of the electrode pair may be employed to read the absolute level of
oxygen concentration and in addition, function to establish the
difference in oxygen concentration caused by glucose oxidation. In
view of the fact that temperature may vary, a thermistor may be
included in the electrode system to make temperature corrections
for reason that the absolute oxygen reading from either a
polarographic or galvanic oxygen electrode is extremely sensitive
to temperature and the rate of glucose oxidation is temperature
sensitive.
Inventors: |
Bessman; Samuel P. (Los
Angeles, CA), Layne; Ennis C. (San Gabriel, CA), Thomas;
Lyell J. (San Pedro, CA) |
Family
ID: |
23223701 |
Appl.
No.: |
06/315,282 |
Filed: |
October 27, 1981 |
Current U.S.
Class: |
600/347;
204/403.14; 205/777.5; 600/549 |
Current CPC
Class: |
A61B
5/14865 (20130101); C12Q 1/006 (20130101); A61B
10/00 (20130101) |
Current International
Class: |
A61B
5/00 (20060101); A61B 10/00 (20060101); C12Q
1/00 (20060101); A61B 005/00 () |
Field of
Search: |
;128/632,635
;204/195B |
References Cited
[Referenced By]
U.S. Patent Documents
Other References
Kondo et al., "Trial of New Vessel Access Type Glucose Sensor for
Implant. Art. Pancreas in Vivo"; Trans. Am. Soc. Artif. Intern.
Organs, vol. XXVII, 1981, pp. 250-252. .
Pagurek et al., "Adaptive Control of Human Glucose-Regulatory
System"; Med. and Biol. Engr., vol. 10, No. 6, 11-1972, pp.
752-761. .
Chang et al., "Validation and Bidengr. Aspects of an Implant.
Glucose Sensor"; Trans. Am. Soc. Artif. Int. Organs; vol. XIX,
1973, pp. 352-360. .
Chua et al., "Plasma Glucose Measurement with the Yellow Springs
Glucose Analyzer"; Clin. Chem. 24/1, pp. 150-152, 1978. .
Danielsson et al.; "Use of an Enzyme Thermistor in Continuous
Measurements and Enzyme Reactor Control"; Biotechnology and
Bioengineering, vol. 21, pp. 1749-1766, 1979. .
Bessman et al.; "Implantation of a Closed Loop Artificial Beta Cell
in Dogs"; Trans. Am. Soc. Artif. Inter. Organs; vol. 28, 1981, pp.
7-18. .
Mahler et al., "Kinetics of Enzyme-Catalyzed Reactions"; Biol.
Chem.; 1966, pp. 237-241. .
Clark et al.; "Differential Anodic Enzyme Polarography for the
Measurement of Glucose"; Adv. Exp. Med. Biol.; 37A, pp. 127-133,
1973. .
Updike et al., "The Enzyme Electrode"; Nature, vol. 214, 6-1967,
pp. 986-988. .
Wingard et al., "Immobilized Enzyme Electrodes for the
Potentiometric Measurement of Glucose Concentration"; Journ. of
Biomed. Mat'ls Res., vol. 13, pp. 921-935, 1979. .
Layne et al.; "Continuous Extracorporeal Monitoring of Animal Blood
Using the Glucose Electrode"; Diabetes 25, pp. 81-89,
2-1976..
|
Primary Examiner: Howell; Kyle L.
Assistant Examiner: Sykes; Angela D.
Attorney, Agent or Firm: Fidelman, Wolffe & Waldron
Claims
We claim:
1. In a method for measuring the glucose content in body fluids by
ascertaining the output differential between a pair of adjacent
oxygen sensors placed into contact with body fluids, one of said
oxygen sensors being unaltered, the other of said oxygen sensors
containing glucose oxidase positioned between said other sensor and
body fluids placed into contact with said other sensor, whereby the
sensor pair measures an oxygen content differential in body fluids
placed into contact with the sensor pair, said measured
differential corresponding to the extent oxygen in the body fluids
has been removed by oxidation of glucose in the body fluids, being
thereby a reading for the glucose content in the body fluids, the
improvement which comprises measuring the level of oxygen in the
body fluids and adjusting said measured differential according to
the level of oxygen, whereby the adjusted measured differential
constitutes a more accurate reading for the glucose content in the
body fluids.
2. The method of claim 1 wherein said improvement further comprises
measuring the level of oxygen in the body with the unaltered oxygen
sensor.
3. The method of claim 1 including adjusting said measured
differential according to the temperature at which measurement is
made.
4. The method of claim 1 wherein said sensors are oxygen electrodes
and their adjusted current output differential constitutes the
glucose content measurement.
5. In a glucose sensor for measuring the glucose content in body
fluids comprising a pair of adjacent oxygen sensors, one of said
oxygen sensors being unaltered and the other of said oxygen sensors
formed into a glucose sensor by inclusion therewith of glucose
oxidase positioned between said other sensor and any body fluids
placed into contact with said other sensor, said pair of sensors
being interconnected to provide an output differential that
constitutes a reading for the glucose content in body fluids placed
in contact with the pair of sensors, the improvement which
comprises having said glucose sensor both to measure the oxygen
concentration in body fluids placed in contact with the pair of
sensors and to adjust the said output differential of the sensor
pair according to the oxygen concentration, whereby a more accurate
reading for glucose content is provided.
6. The glucose sensor of claim 5 further comprising the unaltered
oxygen sensor providing said measurement of the oxygen
concentration and functioning as one of said oxygen sensor
pair.
7. The glucose sensor of claim 5 including means therein to sense
the temperature level of the body fluids and to adjust the output
differential of the pair of oxygen sensors for the temperature at
which measurement is made.
8. The glucose sensor of claim 5 wherein said oxygen sensors are
electrodes and their adjusted current output differential
constitutes the glucose content measurement.
Description
This invention relates to a glucose sensor, and, in particular, to
an implantable glucose sensor.
BACKGROUND OF THE INVENTION
Measurement of glucose in solution in body fluids is usually
carried out by measuring the consequence of oxidation of the
glucose in the body fluid. This oxidation may be catalyzed by an
enzyme, e.g., glucose oxidase.
The glucose oxidase reaction is as follows: ##EQU1##
Several configurations of electrodes using this reaction which
might be applied to body fluids have been suggested to the art.
According to a suggestion made by Clark et al., a polarographic
oxygen electrode is placed behind a chamber filled with a solution
of glucose oxidase. The outer wall of the chamber is permeable to
glucose and oxygen, and the wall of the chamber facing the oxygen
electrode is permeable only to oxygen. When a glucose solution is
applied to the outer membrane, the glucose oxidase reaction
consumes oxygen, diminishing the reading of the oxygen electrode as
some function of the glucose concentration. For details of this
suggestion, see L. C. Clark, Jr. and E. W. Clark. "Differential
Anodic Enzyme Polarography for the Measurement of Glucose", Adv.
Exp. Med. Biol. 37A, 127-133 (1973).
According to a suggestion made by Updike and Hicks, two
polarographic oxygen electrodes are placed behind two cylinders of
gel. One cylinder of gel contains entrapped vacuoles of glucose
oxidase solution and the other acts as a control. The amount of
glucose in a solution is determined as a function of the difference
in the reading of the two electrodes, only one of which is affected
by the presence of glucose in a similar manner to the Clark
electrode. See Updike, S. J. and Hicks, G. P. "The enzyme
electrode, a miniature chemical transducer using immobilized enzyme
activity". Nature 214, 986 (1967) and also Wingard, Jr., L. B.,
Schiller, J. G., Wolfson, Jr., S. K., Liu, C. C., Drash, A. L. and
Yao, S. J. "Immobilized Enzyme Electrodes for the Potentiometric
Measurement of Glucose Concentration". J. Biomed. Mat. Res. 13,
921-935, (1979).
Another suggestion is for a differential electrode using two
galvanic oxygen cells, one of which is a reference and the other
covered by a plastic membrane containing covalently bonded glucose
oxidase in a closed loop "artificial beta cell" as well as for
other measurements. See Layne, E. C., Schultz, R. D., Thomas, Jr.,
L. J., Slama, G., Sayler, D. F. and Bessman, S. P. "Continuous
Extracorporeal Monitoring of Animal Blood Using the Glucose
Electrode". Diabetes 25, 81-89 (1976).
Still another suggestion is for an electrode which uses glucose
oxidase to form peroxide which is read directly using a
polarographic cell. See Chua, K. S. and Tan, F., "Plasma Glucose
Measurement with the Yellow Springs Glucose Analyzer". Clin. Chem.
24, 150-152 (1978).
One suggested measurement for glucose relies on heat generated by
the above reaction. Suggested has been an electrode which measures
temperature of the glucose oxidase using a very sensitive
thermistor covered with a layer of glucose oxidase. See Danielsson,
B., Mattiason, B., Karlsson, R. and Winquist, F. "Biotechnology and
Bioengineering," Vol. XXI, Pg. 1749-1766 (1979) John Wiley and
Sons, Inc.
One way or another, all of the suggestions made heretofore, such as
those alluded to above, assume that the actual level of dissolved
oxygen in the body fluid is of no significant consequence to the
glucose measurement since only the changes in one reactant or
another, as indicated by oxygen utilization or formation of
peroxide, by generation of heat, or of gluconic acid are indicative
of glucose concentration.
However, availability of oxygen for reaction with glucose, i.e.,
actual oxygen concentration in the body fluid is a limiting factor
for the glucose oxidation reaction. Yet, as has been pointed out
above, the art has not heretofore accounted for limitations imposed
by availability of oxygen on the electrode systems which depend on
glucose oxidation for measuring glucose content in body fluid.
THE INVENTION
The present invention provides a method and apparatus for more
accurate measurements of the glucose content in body fluids by
sensing the absolute level of oxygen concentration in the fluid and
correcting the output differential measurement indicative of the
glucose content in the fluid according to the absolute level of
oxygen.
In the two electrode systems known to the art, the unaltered oxygen
electrode of the electrode pair may be employed and preferably is
employed to read the absolute level of oxygen concentration in
addition to functioning to establish the difference in oxygen
concentration caused by glucose oxidation.
In view of the fact that temperature may vary in the body, a
thermistor should be included in the electrode system to make
temperature corrections for two reasons--first, the absolute oxygen
reading from either a polarographic or galvanic oxygen electrode is
extremely sensitive to temperature--second, the rate of glucose
oxidation is temperature sensitive. Appropriate means for
corrections of electrode readings must therefore be incorporated in
the electrode system.
DISCUSSION OF THE INVENTION
For further understanding of this invention, reference is now made
to the attached drawings wherein:
FIG. 1 is a graph illustrating sensor current output plotted
against glucose content for body fluids of varying oxygen
levels;
FIG. 2 is a graph illustrating the current output difference
between an electrode pair plotted against glucose content at
varying oxygen levels;
FIG. 3 is a plan view of an electrode pair configuration; and
FIG. 4 is a side section view along line 4--4 of FIG. 3.
FIG. 5 is a circuit diagram for an exemplary embodiment of this
invention.
FIG. 1 illustrates the measurement errors which may arise because
the oxygen signal differential ususally taken as the measure of
glucose concentration varies with the initial oxygen concentration
in the fluid being tested.
The following test procedure generated the data graphed on FIG.
1.
The test apparatus consisted of a 15 ml water jacketed test chamber
with the water pumped into the jacket from a thermostatically
temperature controlled bath. Provision existed for adjusting the
temperature of the bath and therefore of the test chamber.
The test chamber was fitted with a multi-ported cap (four ports)
for entrance of gas, exit of gas, exit of wires to sensor and a
rubber stoppered access port for addition of glucose solution. The
chamber was equipped with a magnetic stirrer.
A known volume of water (10 to 15 ml) was added to the chamber and
the galvanic glucose-oxygen sensor submerged. A commercial mixture
of oxygen-nitrogen was vigorously bubbled into the fluid at the
bottom of the chamber exiting at the top.
Glucose concentration was altered by the successive addition of 50
.mu.l aliquots of concentrated glucose solution to the chamber.
After mixing, a 50 .mu.l aliquot of the chamber contents was
removed for chemical analysis.
Sensor current was measured as voltage drop across a 20,000 Ohm
load resistor. At each measurement point the sensor was allowed to
equilibrate, evidenced by constant current output for at least 20
minutes.
Looking now to FIG. 1, it may be seen that the oxygen electrode
provides a steady level output in Nano amperes regardless of
variations in glucose concentration. However, the output of the
oxygen electrode depends on the oxygen concentration in the
oxygen-nitrogen mixture, as may be seen by the parallel horizontal
lines for the different 10%, 15% and 21% oxygen content levels. As
may be seen from the curves plotted in FIG. 1, the output of the
glucose electrode under the different oxygen concentration
conditions is clearly some function of the oxygen concentration as
well as of the glucose concentration. An output of 300 na from the
glucose electrode represents a glucose concentration of 55 mg% in
15% oxygen, but 200 mg% at 21% oxygen.
That the differential in electrode output from the two electrodes
is not representative only of the glucose concentration may be seen
on FIG. 2, whereon the differences in output at 10%, 15% and 21%
oxygen in the oxygen-nitrogen mixture are plotted against glucose
concentration.
The reading for 200 mg% glucose is about 50 na when oxygen
concentration is 10%, about 100 na when oxygen concentration is
15%, and about 200 na when oxygen concentration is about 21%.
Conversely, a differential in output of about 75 na could therefore
be indicative of a glucose concentration somewhere between 55 to
200 mg% and a more exact estimate of glucose concentration requires
ascertaining ambient oxygen concentration more closely than the
about 5%-15% range that exists in body fluids.
The wide range of uncertainty regarding glucose concentration shown
by the data plotted on FIGS. 1 and 2 presents a serious problem in
treatment of diabetics. For example, if a dual electrode device
were used to sense arterial blood glucose level in an animal or
human patient, in face of arterial blood oxygen variations between
21% and 10% oxygen depending upon respiration efficiency,
interpretation of the 50 na sensor signal as 200 mg% glucose would
indicate the need to administer insulin, whereas interpretation of
the sensor signal as 55 mg% glucose makes the reading an absolute
contraindication for insulin administration.
Since the differential output is demonstrated by FIG. 2 to be some
function of the oxygen concentration, conversion of the
differential output into a more accurate measurement for glucose
concentraton should be made, and by practice of this invention the
differential output is corrected for oxygen concentration. Oxygen
concentration may be read by a reference electrode, or in preferred
embodiments of this invention on the fly, so to speak, by the
(unaltered) oxygen electrode of the oxygen electrode-glucose
oxidase containing electrode pair. The additional information as to
ambient oxygen concentration from the oxygen sensitive electrode(s)
employed is coupled with the difference in electrical output from
the glucose sensitive electrode and the oxygen electrode for
measurement of glucose concentration as a function of the two
outputs.
The outputs from a glucose oxidase containing electrode and the
oxygen electrode(s) are sufficient to estimate glucose
concentration to meaningful accuracy at a constant temperature.
Mathematical techniques are available empirically or theoretically
to generate functions which, for example, fit the data provided on
FIGS. 1 and 2, to meaningful accuracy within the precision of the
data. For example, the reciprocal of the current difference between
the two sensors has roughly a linear relation to the reciprocal of
the glucose concentration. However, the constants of linearity are
different for each oxygen concentration. The actual function used
to correct for oxygen concentration employed may be selected for
simplicity, accuracy or convenience.
In making the correction, data from the oxygen-only sensor is used
to develop the difference signal and then either is used again or
is taken from the added (control) oxygen electrode for correcting
the difference signal so as to balance out the effect of the oxygen
concentration level upon the activity of the glucose oxidase
enzyme.
As an example, FIG. 2 illustrates one calculated correction which
has less than a 10% error from the observed results over the
clinically interesting range of glucose concentration from 50 to
150 mg % glucose under conditions wherein the ambient oxygen
concentration was 21%, 15% and 10%.
The experimental data plotted on FIG. 2 (solid squares) are the
current differences measured between the oxygen-sensitive output
(Ro) and the glucose-sensitive output (Rg). This difference (D)
when plotted against glucose concentration (G) yields a hypothetic
function typical of enzyme kinetics and the double-reciprocal plot
is roughly linear. Thus:
Where B.sub.1 is the slope, A.sub.1 the intercept and D=Ro-Rg At
21% oxygen A.sub.1 =1.79.times.10.sup.-3 and B.sub.1 =0.637. For
any given difference between oxygen current (Ro) and glucose
current (R.sub.g) measured at 21% oxygen, the corresponding glucose
concentration can be calculated from equation (1).
Similar linear expressions can be derived for 15% and 10% oxygen
but with different slopes and intercepts. It is found empirically
that the slopes and intercepts vary linearly with the logarithm of
the oxygen reading (ro). Thus:
A.sub.2, B.sub.2, A.sub.3 and B.sub.3 are empirically determined
for each sensor. In the instance of the experimental data test
results plotted in FIGS. 1 and 2:
The calculated results (x--x) plotted on FIG. 2 were obtained by
deriving A.sub.1 and B.sub.1 from equations 3 and 4 utilizing the
reading of the oxygen sensor. A.sub.1 and B.sub.1 are then employed
in equation (2) to calculate glucose concentration from the
differences observed between the oxygen and the glucose sensor.
In addition to the graphic presentation of experimental and
calculated results plotted on FIG. 2, the experimental and
calculated results have been tabulated and form part of the data
hereinafter provided in Table I.
The glucose oxidase glucose sensor is temperature sensitive. For
example, Table I shows also representative measurements taken over
the temperature range from room-temperature to body temperature.
Output of the oxygen sensitive area (R.sub.o) varies from 218 to
523 na and the glucose sensitive area varies also. The enzyme
glucose oxidase is known to be temperature sensitive. Estimation of
variations in glucose concentration with glucose sensor devices
requires adjustment for temperature, if temperature variation
between successive measurements are expected to occur, as for
instance, between calibration of a device at ambient temperature,
but measurements at body temperature.
TABLE I
__________________________________________________________________________
GLUCOSE CONCENTRATION VS. SENSOR OUTPUT AT DIFFERENT TEMPERATURES
OBSERVED OXYGEN READING TEMPERATURE CORRECTED TO CALCULATED
CORRECTED.sup.(5) 37.degree. C..sup.(3) Glucose.sup.(4) GLUCOSE
Temp Glucose R.sub.g.sup.(1) R.sub.o.sup.(2) 37.sub.R.sbsb.g
37.sub.R.sbsb.o G.sub.0 (mg %) G.sub.ot (mg %)
__________________________________________________________________________
37 50 400 523 400 523 65.2 65.2 100 335 514 335 514 112 112 150 283
500 283 500 162 162 200 262 497 263 497 186 186 29 50 273 308 441
498 26.1 54 100 238 301 385 487 53.7 112 200 196 301 318 487 107
222 23.3 50 205 218 418 445 13.9 36.3 100 186 218 378 445 38 99.5
150 167 220 340 449 67.4 176 200 154 220 313 449 89.1 233
__________________________________________________________________________
.sup.(1) R.sub.g = output of glucose sensitive area .sup.(2)
R.sub.0 = output of oxygen sensitive area at 21% ambient oxygen
.sup.(3) 37.sub.R.sbsb.x = [8.929-5.0 (log T.sub.c)] R.sub.x where
x = g or o and T.sub.c = temperature in centigrade degrees .sup.(4)
Calculated as for FIG. 2 .sup.(5) G.sub.ot = G.sub.o ln (37 -
T.sub.c)
A preferred embodiment of this invention, i.e., the device
illustrated by FIGS. 3 and 4, employs a glucose sensor 10, which
contains a glucose sensitive area 14, an oxygen sensitive area 16
and a means for sensing ambient temperature. The temperature sensor
might, for example, be the thermistor 18, as is illustrated, or
alternatively a thermometer, or a pressure sensitive device, a
heated or cooled reference area, or a volume sensitive device, or
other known to the art sensor means suited to measure temperature
changes.
Output of the temperature sensor 18 is used to correct the glucose
sensitive, oxygen sensitive output and glucose oxidase activity to
some standard reference condition. It is not required that the
temperature conditions of use and calibration or reference
conditions be the same. The correction function may be obtained
from theoretical considerations or from an empirical fit to the
sensor output versus T.degree. curve. Here, too, the function may
be selected for simplicity, accuracy or convenience. In Table I is
shown an example of such a correction.
In the exemplary data tabulated below in Table I, the sensor
readings observed (Col. 1 and 2) were corrected to 37.degree. C. by
the relationship
Where T is the centigrade temperature of observation and R.sub.T is
the sensor reading at that temperature. This relation was selected
for convenience and has up to about a 10% error.
The sensor readings were then utilized in equation 2 to calculate
an intermediate value for glucose concentration (Col. 4, Table I)
which was corrected for the effect of temperature on the enzyme
activity by the equation
Where
G.sub.T is the intermediate calculated glucose value
T is the temperature of observation
In the special case where T.degree.=37.degree., i.e., body
temperature, no correction is necessary. To repeat, the function
(equation 6) and the reference temperature (37.degree.) were
selected for convenience and to illustrate practice of this
invention.
In summary, the glucose sensors contemplated for practice of this
invention, may be used as an implantable or external sensor of
glucose based on glucose oxidase utilization of oxygen in the
presence of glucose. It is required that the sensor have an oxygen
sensitive area in addition to a glucose sensitive one, and
desirably an independent temperature sensitive output. Corrections
for temperature and oxygen concentration to the sensor output
signal are applied by analog or digital means, which per se are
known to the art, so as to make the sensor output an accurate
reading of glucose concentration.
The sensor device may be calibrated under conditions different from
use or from reference conditions. For example, a sensor intended
for use implanted in the human body at 37.degree. C. and 3% oxygen
can be calibrated at room temperature and atmospheric (20%)
oxygen.
Practice of this invention is not limited to the sensors herein
described nor to the sensor measurement modes herein described.
Another embodiment of the principles and practice of this invention
may be in the polarographic measurement of peroxide generation by
glucose oxidase as the glucose reactive area of an electrode as has
been suggested by Chua et al. supra. In such system, the net
peroxide formed at a particular glucose concentration is also a
function of the oxygen concentration and temperature and for
accuracy must be corrected, for example, by including an oxygen
sensitive area and appropriate known-to-the-art circuitry. Although
correction for oxygen concentration is not absolutely necessary
when the electrode is used in air or in any environment higher than
150 mm p0.sub.2, at the low and variable p0.sub.2 encountered even
in flowing blood the separate correction herein described using a
reference oxygen measurement should be made for accurate
measurement of glucose concentration.
Another embodiment of practice of this invention may be in the
measurement of the heat capacity of the reaction of glucose oxidase
with glucose as has been suggested by Danielson et al. (supra). The
reference temperature is read from a thermal sensitive area and the
glucose sensitive area is an equivalent thermal sensitive area with
attached glucose oxidase. In this instance the concentration of
glucose is read as a function of the temperature differential
between the reference and the glucose sensitive areas. This thermal
reading for glucose concentration may be corrected as has been
described above according to the temperature corrected oxygen value
reading from an oxygen sensitive area, with appropriate
known-to-the-art circuitry.
Correction for oxygen concentration as described herein may be
applied to all glucose electrodes dependent on oxidation, e.g.,
fuel cells as suggested by Bessman, S. P. and Schultz, R. D. "Sugar
Electrode Sensor for the `Artificial Pancreas`". Horm. Metab. Res.
4,413-417 (1972). For accurate measurement of glucose
concentration, it is not enough to use a reference fuel cell and
measure differences alone. As long as the sensing mechanism is not
exposed to an excess of oxygen, which means in all environments
within the body including arterial blood, every sensor which
depends on oxidation is dependent also upon the oxygen tension.
For further understanding of this invention and the practice
thereof, the circuit diagram for one preferred mode of this
invention has been illustrated on FIG. 5 and is hereinafter
described.
Referring now to FIG. 5, it may be seen that currents from oxygen
electrode 13 and glucose electrode 15 are converted to oxygen and
glucose voltages, respectively, by amplifiers 21 and 22. These
oxygen and glucose voltages are temperature compensated by outputs
from amplifier 23. For instance, the oxygen output voltage of
amplifier 21 (via potentiometer R3) and a temperature compensating
output of amplifier 23 (via potentiometer R11) are multiplied in
multiplier 31 to yield a temperature corrected output voltage,
O.sub.2 (T.C.), as indicated at the output of multiplier 31.
Correspondingly, the glucose voltage output of amplifier 22 (via
potentiometer R6) and a temperature compensating output from
amplifier 23 (via a potentiometer R12) are multiplied in multiplier
32 to yield a temperature compensated glucose voltage, G. (T.C.),
as indicated at the output of multiplier 32. This temperature
correction occurs due to thermistor R9, appropriately trimmed by
R10, causing the output of amplifier 23 to vary inversely to the
outputs of amplifiers 21 and 22 (oxygen sensitive current only)
with temperature. The temperature corrected glucose and oxygen
voltages are subtracted at the differential denominator input of
divider 41 and divided into a voltage arbitrarily set by
potentiometer R18. The output from potentiometer R18 may be made
equal to unity, for convenient subsequent calculation, by setting
the potentiometers R19, R20, R25 and R30 (outputs of which
correspond to constants B.sub.2, B.sub.3, A.sub.3 and A.sub.2).
Accordingly, the output from divider 41 will be 1/D, (from the left
side of equation[1]).
The derived constants A.sub.1 and B.sub.1 are obtained, with the
notation (T.C.) omitted from the remaining computation for
convenience, as follows: The output of multiplier 31 is converted
to its logarithm, base 10, by LOG module 50 to yield LOG O.sub.2.
To compute A.sub.1, the output from this LOG module 50 is, in turn,
multiplied in multiplier 33 by the voltage generated at R19 to
yield B.sub.2 LOG O.sub.2. This output from multiplier 33 is then
added to the voltage generated at R30, by amplifier 25, to yield
A.sub.1 =B.sub.2 LOG O.sub.2 +A.sub.2 (equation 3). In a similar
manner, A.sub.1 B.sub.1 is computed by multiplying the output of
LOG module 50, in multiplier 35, by the voltage generated at R20 to
yield B.sub.3 LOG O.sub.2 which, in turn, is added to the voltage
generated at R25, in amplifier 26, to yield A.sub.1 B.sub.1
=B.sub.3 LOG O.sub.2 +A.sub.3 (a form of equation 4). This output
from amplifier 26 (B.sub.1 A.sub.1) is then divided, in divider 43,
by the output of amplifier 25 (A.sub.1) to yield B.sub.1. The
output from divider 41 (1/D) is applied to the positive side of the
differential denominator input of divider 42 and the output from
amplifier 25 (derived constant A.sub.1) is applied to the negative
side of this denominator input, while the output of divider 43
(derived constant B.sub.1) is fed to the numerator input of divider
42. Thus, the output of divider 42 (equation 2) is the value of
measured glucose concentration correction for oxygen concentration.
Temperature correction for glucose oxyidaze enzyme activity is
accomplished, similar to the previous temperature correction, at
multiplier 35, by appropriately trimming the output of amplifier 24
with potentiometer R16. The output of amplifier 24 is fed to one
input of multiplier 34 and that of divider 42 is fed to the other
input of multiplier 34, yielding an output which gives the measured
glucose sensitive current of the sensor corrected to a specified
temperature and oxygen concentration.
Typical active components for a prototype include the following:
LF355FET high impedance input operational amplifiers for components
21-24; LM741 operational amplifiers for components 25 and 26; AD532
integrated circuit multipliers for components 31-35; AD535
integrated circuit dividers for components 41-43; and AD755 LOG
antilog amplifier for LOG module 50. Thermistors R9 and R15 may be
YSI #44004 Thermistors rated 2.2K.OMEGA. at 25.degree. C.
* * * * *